Parkinson's disease is a neurodegenerative disorder characterized by selective degeneration and cell death of dopaminergic neurones in the substantia nigra region of the brainstem. Parkinson's disease is generally considered to be sporadic and of unknown etiology. Over the past five years, however, a handful of mutations in the leucine rich repeat kinase 2 (LRRK2) gene have been linked to Parkinson's disease (WO2006068492 and WO2006045392). The G2019S mutation co-segregates with autosomal dominant parkinsonism and accounts for about 6% of familial Parkinson's disease cases and 3% of sporadic Parkinson's disease cases in Europe (Gilks et al., 2005, Lancet, 365: 415-416; Jaleel et al., 2007, Biochem J, 405: 307-317). LRRK2 is a member of the ROCO protein family and all members of this family share five conserved domains. The G2019S mutation occurs in the highly conserved kinase domain and it has therefore been postulated that the G2019S mutation may have an effect on kinase activity (WO2006068492). It has since been verified that this mutation increases the Vmax of LRRK2 for the non-natural, in vitro, substrates, moesin and the LRRKtide peptide (Jaleel et al., 2007, Biochem J, 405: 307-317). Amino acid substitutions at a second residue R1441 are also associated with Parkinson's Disease (reviewed in Paisan-Ruiz 2009, Hum. Mutat. 30: 1153-1160) and have also been shown to elevate LRRK2 kinase activity via decreasing the rate of GTP hydrolysis by the GTPase domain of LRRK2 (Guo et al., 2007 Exp Cell Res. 313: 3658-3670; West et al., 2007 Hum. Mol Gen. 16: 223-232). Over-expression of the mutant protein LRRK2 R1441G is reported to cause symptoms of Parkinson's disease and hyperphosphorylation of Tau in transgenic mouse models (Li, Y. et al. 2009, Nature Neuroscience 12: 826-828). This LRRK2 driven phenotype is also characterized by diminished dopamine release, suggesting that inhibitors of LRRK2 would be expected to positively regulate dopamine release. These data suggest that novel LRRK2 inhibitors of kinase catalytic activity could be useful for the treatment of Parkinson's disease, including idiopathic Parkinson's disease and familial Parkinson's disease, particularly familial Parkinson's disease in patients expressing LRRK2 kinase bearing the G2019S mutation or the R1441G mutation. In addition, LRRK2 inhibitors may have potential utility in treatment of other conditions characterized by diminished dopamine levels such as withdrawal symptoms/relapse associated with drug addiction (Rothman et al., 2008, Prog. Brain Res, 172: 385), and Tauopathy diseases characterized by hyperphosphorylation of Tau such as argyrophilic grain disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy and inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) (Goedert, M and Jakes, R (2005) Biochemica et Biophysica Acta 1739, 240-250).
Two further mutations in LRRK2 have been identified that are clinically associated with the transition from mild cognitive impairment (MCI) to Alzheimer's disease (WO2007149798). These data suggest that inhibitors of LRRK2 kinase activity could be useful for the treatment diseases such as Alzheimer's disease, other dementias and related neurodegenerative disorders.
In an experimental model of Parkinson's disease in marmosets an elevation of LRRK2 mRNA is observed in a manner that correlates with the level of L-Dopa induced dyskinesia (Hurley, M. J et al., 2007 Eur. J. Neurosci. 26: 171-177). This suggests that LRRK2 inhibitors may have utility in amelioration of such dyskinesias.
Evidence is also emerging of roles for LRRK2 in regulating neuronal progenitor differentiation in vitro (Milosevic, J. et al., 2009 Mol. Neurodegen. 4: 25), suggesting that inhibitors of LRRK2 may have utility in production of neuronal progenitor cells in vitro for consequent therapeutic application in cell based-treatment of CNS disorders.
Parkinson's disease patients bearing LRRK2 G2019S mutation have been reported to display increased frequency of non-skin cancers, including renal, breast, lung, prostate cancers as well as acute myelogenous leukemia (AML). Given that G2019S mutation in LRRK2 is reported to increase catalytic activity of the LRRK2 kinase domain, it is anticipated that there may be utility in small molecule inhibitors of LRRK2 for treatment of cancers, especially those of kidney, breast, lung, prostate (e.g. solid tumors) and blood (e.g. AML; Saunders-Pullman et al., 2010, Movement Disorders, 25:2536-2541). Amplification and overexpression of LRRK2 has also been reported in papillary renal and thyroid carcinomas, where co-operativity between LRRK2 and the MET oncogene may promote tumor cell growth and survival (Looyenga et al., 2011 PNAS 108: 1439-1444).
Meta-analysis of three genome wide associated scans for Crohn's disease identified a number of loci associated with the disease, including the locus containing the LRRK2 gene (Barrett et al., 2008, Nature Genetics, 40: 955-962). More recently, evidence has emerged suggesting that LRRK2 is an IFN-γ target gene that may be involved in signaling pathways relevant to Crohn's disease pathogenesis (Gardet et al., 2010, The Journal of Immunology, 185: 5577-5585). These findings suggest that inhibitors of LRRK2 may have utility in the treatment of Crohn's disease.
As an IFN-γ target gene LRRK2 may also play a role in T cell mechanisms that underlie other diseases of the immune system such as Multiple Sclerosis and rheumatoid arthritis. Further potential utility of LRRK2 inhibitors comes from the reported finding that B lymphocytes constitute a major population of LRRK2 expressing cells (Maekawa et al. 2010, BBRC 392: 431-435), This suggests that LRRK2 inhibitors may be effective in treatment of diseases of the immune system for which B cell depletion is, or may be, effective—such as lymphomas, leukemias, multiple sclerosis (Ray et al., 2011 J. Immunol. 230: 109), rheumatoid arthritis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura (ITP), Evans syndrome, vasculitis, bullous skin disorders, type 1 diabetes mellitus, Sjogren's syndrome, Devic's disease and inflammatory myopathies (Engel et al., 2011 Pharmacol. Rev. 63: 127-156; Homam et al., 2010 J. Clin. Neuromuscular Disease 12: 91-102)